Cerebrospinal Fluid Alzheimer Markers in Depressed Elderly Subjects with and without Alzheimer's Disease

Depression and Alzheimer’s disease (AD) are among the most common clinical diagnosis in older people. The relation between depression and AD is complex: depression has been shown to be a risk factor, prodromal symptom and a consequence of AD. Increased understanding of the underlying mechanisms of depression in AD may lead to early detection and differential diagnosis, and is crucial for development of novel and mechanism-based treatments. The first two studies of this doctoral thesis are exploring the associations between depressive symptoms and biomarkers of amyloid deposition and neuronal injury in patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI) and AD. The aims of the third study were to describe the use of antidepressants in patients with dementia and to explore the association between mortality risk and the use of antidepressants 3 years before the dementia diagnosis. CAIDE Dementia Risk Score is taking into account midlife risk and protective factors; age, educational level, gender, systolic blood pressure, body mass index, cholesterol level and physical activity and APOE genotyping, and can predict dementia over 20 years. The last study was focused on exploring the associations between CAIDE Dementia Risk Score and biomarkers of amyloid deposition, neuronal injury and small vessel pathology in SCI and MCI patients. Additionally we explored the capacity of CAIDE Dementia Risk Score to predict dementia in a memory clinic population. Data were obtained from Memory Clinic Karolinska University Hospital Huddinge Sweden (Study I, II and IV). In study III, two large national registries were merged: the Swedish Dementia Registry (SveDem) and the Swedish Prescribed Drug Register. In study I, analysis of the three different cerebrospinal fluid biomarkers; amyloid beta (CSF Aβ), total-tau (CSF t-tau), and phosphorylated-tau did not support the hypothesis that more severe amyloid or tau pathologies are associated with more severe depressive symptoms. In contrast, SCI and AD patients with depressive symptoms tended to have lower CSF p-tau levels and, in particular, lower CSF t-tau levels than those without depression, indicating less severe neuronal injury. In study II, we used two different analysis methods of MRI to measure medial temporal lobe atrophy and hippocampus volume. Using manual tracing of the hippocampi we found smaller left hippocampus volume in SCI patients with depressive symptoms compared to those without depressive symptoms. In contrast, AD patients with depressive symptoms had less medial temporal lobe atrophy compared with those without depressive symptoms. In study III, 20,050 patients with incident dementia diagnosed in memory clinics and registered in SveDem were included. Information on the total number of medication and all antidepressants dispensed at the time of dementia diagnosis and at the first, the second and the third year prior to dementia diagnosis was obtained from the Swedish Prescribed Drug Register. During a median follow up of 2 years, 5168 (25.8%) dementia patients died. At the time of dementia diagnosis, 5,004 (25.0%) patients were on antidepressant treatment. Use of antidepressant treatment for 3 consecutive years prior to a dementia diagnosis was associated with a lower mortality risk for all dementia disorders in general and particularly in AD. In study IV, a higher CAIDE Dementia Risk Score was associated with higher CSF t-tau levels, more severe medial temporal lobe atrophy and more severe white matter changes. For the CAIDE score including APOE, a score above 9 points was associated with lower CSF Aβ, more severe medial temporal lobe atrophy and more severe white matter changes. CAIDE Dementia Risk Score (version with APOE) performed better at predicting AD compared with CAIDE Dementia Risk Score without APOE. Conclusion: We found that depressive symptoms in patients with AD and SCI are not associated with more amyloid deposition nor more neuronal injury compared with AD and SCI patients without depressive symptoms. Thus our results are consistent with the hypothesis that the mechanisms underlying depression differ between older people with and without AD. Our results have shown that use of antidepressants in prodromal AD stages is associated with a lower mortality risk. Further longitudinal studies are needed to better understand the associations between the use of antidepressants and mortality risk in dementia

Effects of DHA- Rich n-3 Fatty Acid Supplementation on Gene Expression in Blood Mononuclear Leukocytes: The OmegAD Study

Background: Dietary fish oil, rich in n-3 fatty acids (n-3 FAs), e. g. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), regulate inflammatory reactions by various mechanisms, e. g. gene activation. However, the effects of long-term treatment with DHA and EPA in humans, using genome wide techniques, are poorly described. Hence, our aim was to determine the effects of 6 mo of dietary supplementation with an n-3 FA preparation rich in DHA on global gene expression in peripheral blood mononuclear cells. Methods and Findings: In the present study, blood samples were obtained from a subgroup of 16 patients originating from the randomized double-blind, placebo-controlled OmegAD study, where 174 Alzheimer disease (AD) patients received daily either 1.7 g of DHA and 0.6 g EPA or placebo for 6 months. In blood samples obtained from 11 patients receiving n-3 FA and five placebo, expressions of approximately 8000 genes were assessed by gene array. Significant changes were confirmed by real-time PCR. At 6 months, the n-3 FAs group displayed significant rises of DHA and EPA plasma concentrations, as well as up-and down-regulation of nine and ten genes, respectively, was noticed. Many of these genes are involved in inflammation regulation and neurodegeneration, e. g. CD63, MAN2A1, CASP4, LOC399491, NAIP, and SORL1 and in ubiqutination processes, e. g. ANAPC5 and UBE2V1. Down-regulations of ANAPC5 and RHOB correlated to increases of plasma DHA and EPA levels. Conclusions: We suggest that 6 months of dietary n-3 FA supplementatio

Genes up-regulated by a DHA rich n-3 fatty acid or placebo supplementation.

<p>All values are means±SD.</p><p>^<i>1</i>All genes were significantly up-regulated by the n-3 FAs treatment according to SAM based on 2000 permutations and a false discovery rate of 10%, see microarray data analysis for details.</p><p>^<i>2</i>We analyzed by t-test if genes regulated by n-3 FAs supplementation were also up- or down-regulated in the placebo group. The change for <i>DRG1</i> was significant (p = 0.04).</p><p>^<i>3</i>Significant and</p><p>^<i>4</i>close to significance (p = 0.05–0.06) difference in fold change between the n-3 FAs and placebo group.</p

Donepezil in Alzheimer's disease: what to expect after 3 years of treatment in a routine clinical setting.

Background/Aims: Clinical short-term trails have shown positive effects of donepezil treatment in patients with Alzheimer's disease. The outcome of continuous long-term treatment in the routine clinical settings remains to be investigated. Methods: The Swedish Alzheimer Treatment Study (SATS) is a descriptive, prospective, longitudinal, multicentre study. Four hundred and thirty-five outpatients with the clinical diagnosis of Alzheimer's disease, received treatment with donepezil. Patients were assessed with Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), global rating (CIBIC) and Instrumental Activities of Daily Living (IADL) at baseline and every 6 months for a total period of 3 years. Results: The mean MMSE change from baseline was positive for more than 6 months and in subgroups of patients for 12 months. After 3 years of treatment the mean change from baseline in MMSE-score was 3.8 points (95% CI, 3.0-4.7) and the ADAS-cog rise was 8.2 points (95% CI, 6.4-10.1). This is better than expected in untreated historical cohorts, and better than the ADAS-cog rise calculated by the Stern equation (15.6 points; 95% CI, 14.5-16.6). After 3 years with 38% of the patients remaining, 30% of the them were unchanged or improved in the global assessment. Conclusion: Three-year donepezil treatment showed a positive global and cognitive outcome in the routine clinical setting

Correlation between changes of plasma docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and gene expression.

<p>Changes of plasma DHA, left, and EPA, right, and changes of expression (signal log ratio units) for the <i>ANAPC5</i> (left) and <i>CASP4</i> (right) genes.</p

Plasma values for docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) at baseline and after 6 months.

<p>Individual values are flanked by mean and SD values. Significant increases of DHA and EPA were noted in the n-3 fatty acids (n-3 FAs) group after 6 months, but not in the placebo group.</p

Genes down-regulated by a DHA rich n-3 fatty acid or placebo supplementation.

<p>All values are means±SD.</p><p>^<i>1</i>All genes were significantly down-regulated by the n-3 FAs treatment according to SAM based on 2000 permutations and a false discovery rate of 10%, see microarray data analysis for details.</p><p>^<i>3</i>Significant and</p><p>^<i>4</i>close to significance (p = 0.06–0.09) difference in fold change between the n-3 FAs and placebo groups.</p

CONSORT flowchart. Study design at baseline and after n-3 FA or placebo supplementation to AD patients for 6 months.

<p>AD = Alzheimer's disease, n-3 FA = Omega-3 fatty acid treatment, Placebo = Placebo treatment.</p

Individual messenger RNA measurements in the n-3 fatty acid group.

<p>^<i>1</i>The expression of the target gene was normalized to the LRP10 internal control using the formula 2^{(Ct target calibrator – Ct target sample)}/2^{(Ct LRP10 calibrator – Ct LRP10 sample)} where calibrator is a random sample. Subsequently, fold change was calculated as the ratio between values for 0 and 6 months of n-3 supplementation. Mean±SD values (n = 11).</p><p>^<i>4</i>Near significance.</p